The mathematical analysis of plasma HIV-1 viral load decay after the initiation of antiretroviral therapy has led to a number of important insights abou the dynamics and pathogenesis of HIV infection. With protease inhibitor and reverse transcriptase inhibitor therapies a now classic biphasic decay of HIV RNA was discovered and interpreted using simple viral dynamic models. These models suggested that the first phase was due to the rapid death of productively infected cells and that the second phase was due to the death of long-lived infected cells. Remarkably, the same simple model that accounted for first phase decay when perturbed by therapy could also account for the kinetics of acute infection observed using sparsely sampled data, mostly collected after the viral load peak. Now new data is available that allows us to gain new insights into both acute infection and long-term drug therapy. First, data from acutely infected individuals with very frequent sampling is available from the Early Capture HIV Cohort (ECHO/RV127) study. This study follows participants at high risk for HIV infection twice weekly. Once identified as being HIV-infected, individuals are sampled twice weekly for a month, then weekly for another month, then monthly for 5 years in order to obtain information on clinical consequences. The original model of acute infection dynamics fits much of this data poorly, suggesting acute infection kinetics are not yet fully understood, particularly with regard to immune system influences. Secondly, new frequently collected data from an ACTG study in which treatment nave patients were given raltegravir plus emtricitabine/tenofovir uncovered that the first phase has two parts: a rapid phase of decay over the first few days of therapy (phase 1a) followed by a slower phase 1b. Using single copy assays, a very slow 3rd phase of decay (t1/2=39 wks) followed by a 4th phase of stable viremia has been identified, the origins of which are not understood. Here we aim to uncover through modeling the biological basis of acute infection dynamics and these newly observed short and long term HIV dynamics under therapy, and their implications for treatment and viral eradication. PUBLIC HEALTH RELEVANCE: This work will increase our understanding of acute HIV infection dynamics and the immunological factors that influence early infection and the establishment of viral reservoirs. Our proposed work will provide new insights into the compartments responsible for the kinetics of decay observed with raltegravir and into the reservoirs that prevent long-term viral eradication with current therapies.